Hydantoins and methods of obtaining the same



Patented July 23, 1946 UNITED STAT-ES RATENT- OFF-ICE Loren M. Long,Detroit, Mich., assignor to Parke, 1 J Davis & Company,-Detroit Mich., acorporation i of Michigan Nobrawing. Application seet ifiei as, 1344,

l Serial No. 555,759

8 Claims. (01. zoo-309.5)"

The invention relates to'a new class'of chemical compounds which arevaluable for therapeutic use, especially as anticonvulsants havingrelatively high anticonvulsant activity combined with low toxicity.

The compounds of the, invention have-the general formula, e

where R is a straight, branched, or cyclicE-alkyl radical or an aryl oraralkyl radical such that the total number of carbon. atoms in R is noti more than 7. M of this formula represents a member of the classhydrogen and basic elements or groups forming non-toxic salts of thehydantoins, such assodium, calcium, magnesium, ammonium and substitutedammonium, for example, monoand di-alkyl ammonium and, correspondinghydroxy alkyl ammonium. l

The compounds of the invention can be used orally'or by injection. Forexample, the average adult person can start with a dosage of to 1 gramper day orally and increase the dosage slightly thereafter. Thecompounds are without odor when properly purified.

The compounds of thi invention are readily prepared by oxidizing thecorresponding sulfide compounds. The sulfides are made by reacting thecorresponding ketone intermediates of the formula,

. pared by the action of the sodium salt of the appropriate mercaptan'on phenacyl chloride (T. C. Whitner, Jr., and E. E. Reid; J. A. C. S.43, 638 (1921)). They may also be prepared by the reaction of an acidchloride of the formula;

R- S CH2COC1 where R has the same significance asin the formula givenabove for the final product ,,with benzerie After the"sulfidesubstituted}hydantoins have been. madethey' are oxidized atthefsulfidelinkage to the corresponding sulfones'."":This"may be done bymeans of oxidizing agents known .to be efiective in oxidizing sulfidesto sulfones, suchas hydrogen peroxide, chromic acid, peracetic acid andlike oxidizing agents.

The following examples serve to illustrate the invention: Preparation ofp-isobutylmercaptoacetophenone. I

Th method of .Whitn'e'r and 'Reid (J.'A.- C158. 43, 638 a (1921';i's"us'e d'for the preparation of this compound; 30"grams-'(0i75 mole)of sodium hydroxide are dissolved in 500 cc. of %ethano1;

T0 the cooled solution are added 67.5 g." (0.75

mole) of isobutylmercaptan'pn clear solution is f'ormed. rams*(0.'75mole) of phenac'yl chloride are addedand the mixture shaken vigor ously.The mixture becomes warm andforms two liquid layers." It is thenrefluxed forabout thirty 'minutes,cooled, and diluted with two volumesof water; Theproduct is extracted twice with small volumes of ether. Theextracts are combined, washed 'with water, saturated salt solution, anddried over anhydrous magnesium sulfate. The ether is distilled off onthesteam bath and the residue distilled at reduced pressure. 135 grams'ofia" colorless liquid distilling at "C. at 1 mm. is obtained. Theyield is 86.5% of the'theo'retical; n =L5486L l Preparation of5-isobutylmercaptomethyl-5- phenylhydantoin.= l

125 grams of ammonium carbonate are' mixed 93 grams (0.45 mole) orp-isobutylmercapto-Q acetophenone', 40 grams of potassium cyanide, and

phenylhydantoin. E

for an hour.

with 1 liter of 70% ethanol in-a'2 liter, round- 1 bottom-flask..A'large'bore aircondenser is'fitted to the fia'sk which is then heatedat 55-60 C. for about eight hours.

1 The mixture is then evap= 1 orated to about of the original volume onthe steam bath. ,The residue is diluted to about of the original volumewith. water and acidified without iconvulsive seizures'and yet beingalert imentally and p'hysically.-

Other compounds of my invention may be prei-pared by the same methodsillustrated above and using as starting materials, instead of isobutyl.mercaptan, other mercaptans, such as heptyl mercaptans or, in general,mercaptans of forwith concentrated hydrochloric acid -(alloperaei tionsare performed in the :hood); An'.oilipre-' cipitates which quicklysolidifies. The solid is filtered off and dissolved in sodium hydroxide3 solution. The resulting solution 'is charcoaledf 3 and filtered. Thefiltrate is acidified with hy- I drochloric acid, cooled, and filtered.The solid 7 material is recrystallized from ethanol.

yield is'193 grams of 74.5% of the theoretical.

'Preparationi-of 5 -isobutylsulfonomethy1 e5- 20.8 grams (0.75 mole) of5-isobuty1mercapto methyl-Smhenylhydantoin are added to a solu 1. ,tionof 150 .cc. of glacial acetic acidand 38cc.

of acetic .anhydride' vina small Erlenmeyer flask. I

38 cc. of 30%- hydrogen peroxide are then added quickly formsandfgradually warms up. When the temperature-of thesolution' reachesFIG-75C.

the' flask isplaced in an icewater bathin-order to keep .the'temperaturebelow.80,C. When the 1 reaction has slowed down, the "flask 'isremovedfrom the ice water-bathand allowed to stand The reaction products aretrans ferried-t0 alargerflask anddiluted to, five volumes with water.

The desired-hydantoin precipitates as :a; --sol;id. ,After cooling tocorrlpletetheprecipitation, ithe :mixture .is filtered. The :solid'iisThe I -miula, .RS-H, where R may be a straight,

" branched, or cyclic alkyl radical or an aryl or and themixture shakengently. A solution i washed :with water and recrystallized. from 95% 1ethanol; "The *yieldxis .121 grams orx-90% :ofrthe theoretical. P; :221C. N: Calc-d.,'9:0.3;

found, 8.87.

A1 quantity oftthe hydantoin of this example i is dissolved ;in asolution of :one equivalent of dilute :sodium hydroxide solution;Thesolution 1 is then treated with charcoal todecolorize and I clear upthesolution- The mixture with char- 1 coal isfiltered and the filtrateevaporated todryness under reduced pressure at about50 C. The 3 drysolid obtained is the sodium salt of '5-isobutylsulfonomethyl 5phenylhydantoin having 1 the formula, 7

. R HALO This isnn advantage, for example where .a vperson desiresto'carryon his daily tasks onemployment 1 This sodium salt is-aneffective anticonvulsant I whengiven orally anddoes not act as ahypnotic.

aralkyl radical such that the total number of. carbon atoms in His notmore than 7.

'. Further examples of my new hydantoins which I have prepared bymethods such as'described above for the 5-isobutylsulfonomethyl compoundare the following, wherein R stands forthe radical RzOf thegeneral-formula, 1 Y

lvltethylunli The sulfide, intermediates corresponding to leach of theabove: listddisulfones, withjinelting points are" givenlin m .copending,ap-

in each instance, plication. A

Other compounds larly prepared having .alkyl radicals such assecondary-butyl, .1 -methylbutyl, .1 -methylamyl,

l-ethylamyl, or l-methylhexyl as the substituent represented by R in thegeneral formula. I prefer V thebranched chainalkyl derivatives.

-.The sodium salts ,of the above listedhydantoins are prepared'byreacting thehydantoin with sodium hydroxide as set forth in the examplegiven for the isobutyl derivative. Other salts are prepared by using,insteadjof sodium hydroxide, ammonium hydroxide'or an amine to obtainthe corresponding salts indicated in the general where Ris a member ofthe class alkylgcycloa alkyl, aryl, and ara-lkyl radicals having notmore than 7 carbon atoms, andM is a member of the groupconsisting ofhydrogen and non-toxic saltf rm g groups.

of my invention maybesimia 7 2. A compound having the formula,

where R is an alkyl radical having not more than 7 carbon atoms and M isa member of the group consisting of hydrogen and non-toxic salt-forminggroups.

3. A compound having the formula,

I R-S-CH:

where R is a branched chain alkyl radical having not more than 7 carbonatoms and M is a member of the group consisting of hydrogen andnon-toxic salt-forming groups.

4. 5-isobutylsulfonomethyl-5-phenylhydantoin.

5. The sodium salt of 5-isobuty1sulfonomethylfi-phenylhydantoin.

6. Process for obtaining hydantoin compounds which comprises oxidizing ahydantoin of formula R-s-oH, I oo-NH with an oxidizing agent forconverting an organic sulfide to the corresponding sulfone, where R is amember of the class alkyl, cycloalkyl, aryl, and

aralkyl radicals having not more than '7 carbon atoms.

7. Process for obtaining hydantoin compounds which comprises oxidizing ahydantoin of formula

